Compound, Method for Producing the Same, and Method for Producing Oseltamivir Phosphate

ABSTRACT

A compound represented by the following general formula (1), and a method for producing the compound represented by the general formula (1), the method comprising: reacting together a compound represented by the following general formula (2), a compound represented by the following general formula (3), and a compound represented by the following general formula (4): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1  represents any of a protective group of a carboxyl group, and a hydrogen atom, R 2  and R 3  each independently represent any of a protective group of an amino group, and a hydrogen atom, and R 4  represents any of a protective group of a carboxyl group, and a hydrogen atom.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of InternationalApplication PCT/JP2012/055085 filed on Feb. 29, 2012 and designated theU.S., the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a compound and a method for producingthe same, and a method for producing oseltamivir phosphate.

2. Description of the Related Art

There is concern that mutation of an avian influenza virus results in apandemic of new influenza, for example, H5N1 to cause a number ofdeaths. Oseltamivir phosphate (trade name “Tamiflu”), which is anantiviral drug, is known to exhibit a remarkable response to newinfluenza, and the state institutions increasingly stockpile such a drugfor infection prevention. Therefore, the demand for oseltamivirphosphate is rapidly increased across the world and there is a demandfor developing a measure for inexpensively supplying oseltamivirphosphate in a large amount.

As a method for synthesizing oseltamivir phosphate, a method of usingshikimic acid as a starting material is known (see, for example, J. Am.Chem. Soc., 119, 681, 1997).

However, shikimic acid is prepared by extraction or purification fromIllicium verum fruits (star anise), or via fermentation from D-glucoseby E. coli, and there is a problem that such processes aretime-consuming and costly. In addition, it is sometimes difficult tosupply plant materials such as Illicium verum fruits stably.Accordingly, there is a demand for developing a measure for efficientlychemically synthesizing oseltamivir phosphate from an easily availableraw material compound.

For example, a method for synthesizing oseltamivir phosphate from1,3-butadiene and acrylic acid, and an intermediate in the synthesismethod have been proposed (see, for example, J. Am. Chem. Soc., 128,6310, 2006).

In addition, another method for synthesizing an intermediate leading tothe synthesis of oseltamivir phosphate described in J. Am. Chem. Soc.,128, 6310, 2006, which is a diene compound (compound A illustrated inFIG. 1), has been proposed (see, for example, Org. Let., 2008, 10, 815and FIG. 1).

However, such techniques proposed cannot be said to be sufficient fromindustrial aspect, because there are problems that, for example, thesynthesized product is a racemic form, and a thiol compound having ahigh toxicity is stoichiometrically used.

Accordingly, there is currently a demand for providing an intermediateuseful for industrially producing oseltamivir phosphate.

SUMMARY OF THE INVENTION

A problem of the present invention is to solve the conventional problemsto achieve the following object. That is, an object of the presentinvention is to provide an intermediate useful for industriallyproducing oseltamivir phosphate.

A measure for solving the above problem is as follows. That is, acompound of the present invention is represented by the followinggeneral formula (1):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom.

According to the present invention, it is possible to solve theconventional problems to achieve the object, thereby providing anintermediate useful for industrially producing oseltamivir phosphate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is synthesis scheme showing one example of a method forsynthesizing a diene compound as an intermediate leading to thesynthesis of oseltamivir phosphate.

FIG. 2 is the ¹H NMR spectrum of a compound 6-1 in Example 6.

FIG. 3 is the ¹H NMR spectrum of a compound 7-1 in Example 7.

FIG. 4 is the ¹H NMR spectrum of a compound 8-1 in Example 8.

DETAILED DESCRIPTION OF THE INVENTION

Steric configurations of chemical formulae and general formulaedescribed herein and claims represent absolute configurations, unlessparticularly mentioned.

(Compound Represented by General Formula (1) and Method for ProducingSame)

The compound of the present invention is a compound represented by thefollowing general formula (1).

The method for producing the compound of the present invention is amethod for producing the compound represented by the following generalformula (1), the method including a reaction step of reacting together acompound represented by the following general formula (2), a compoundrepresented by the following general formula (3), and a compoundrepresented by the following general formula (4), and further includingother steps if necessary.

<Compound Represented by General Formula (1)>

In the general formula (1), R¹ represents any of a protective group of acarboxyl group, and a hydrogen atom, R² and R³ each independentlyrepresent any of a protective group of an amino group, and a hydrogenatom, and R⁴ represents any of a protective group of a carboxyl group,and a hydrogen atom.

The protective group of a carboxyl group in each of R¹ and R⁴ is notparticularly limited, can be appropriately selected depending on thepurpose, and can be determined with reference to technical books such asGreen et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999,John Wiley & Sons, Inc.

Examples of the protective group of a carboxyl group include an alkylgroup that may have a substituent, a trialkylsilyl group, and an arylgroup that may have a substituent.

Examples of the alkyl group in the alkyl group that may have asubstituent include an alkyl group having 1 to 6 carbon atoms. Examplesof the alkyl group having 1 to 6 carbon atoms include a methyl group, anethyl group, and a tert-butyl group. Examples of the substituent in thealkyl group that may have a substituent include a halogen atom and aphenyl group. Examples of the halogen atom include a fluorine atom, achlorine atom, and a bromine atom. The phenyl group may further have asubstituent. Examples of the substituent of the phenyl group include analkyl group having 1 to 4 carbon atoms, a halogenated alkyl group having1 to 4 carbon atoms, a nitro group, a halogen atom, and an alkoxy grouphaving 1 to 4 carbon atoms.

Specific examples of the alkyl group that may have a substituent includea methyl group, an ethyl group, a tert-butyl group, and a benzyl group.

Examples of the trialkylsilyl group include a trimethylsilyl group and atriethylsilyl group.

Examples of the aryl group in the aryl group that may have a substituentinclude a phenyl group, a naphthalene group, and an anthracene group.Examples of the substituent in the aryl group that may have asubstituent include an alkyl group having 1 to 4 carbon atoms, ahalogenated alkyl group having 1 to 4 carbon atoms, a nitro group, ahalogen atom, and an alkoxy group having 1 to 4 carbon atoms. Examplesof the halogen atom include a fluorine atom, a chlorine atom, and abromine atom.

Among them, an ethyl group is preferable as R¹ in that oseltamivirphosphate can be derived through neither removal nor exchange of theprotective group, namely, ethyl ester in oseltamivir phosphate can beintroduced with no need of transesterification, and thus the process forproducing oseltamivir phosphate can be shortened.

Among them, as R⁴, an alkyl group that may have a substituent ispreferable, an alkyl group having 1 to 6 carbon atoms is morepreferable, and a methyl group and an ethyl group are particularlypreferable.

The protective group of an amino group in each of R² and R³ is notparticularly limited, can be appropriately selected depending on thepurpose, and examples thereof include a methoxycarbonyl group, atert-butoxycarbonyl group, a benzyloxycarbonyl group, anallyloxycarbonyl group, a formyl group, an acetyl group, a benzoylgroup, a methyl group, an ethyl group, an allyl group, a benzenesulfonylgroup, and a benzyl group that may have a substituent. In the case whereR² and R³ are taken together to form a protective group of a ringstructure, examples include a phthaloyl group (Phth group).

Examples of the substituent in the benzyl group that may have asubstituent include an alkyl group having 1 to 4 carbon atoms, ahalogenated alkyl group having 1 to 4 carbon atoms, a nitro group, ahalogen atom, and an alkoxy group having a 1 to 4 carbon atoms. Examplesof the halogen atom include a fluorine atom, a chlorine atom, and abromine atom. Examples of the benzyl group that may have a substituentinclude a p-methoxybenzyl group.

Among them, an allyl group and a p-methoxybenzyl group are preferableand an allyl group is more preferable in that they can result in a highyield in the subsequent conversion and are easily deprotected.

The method for producing the compound represented by the general formula(1) is not particularly limited and can be appropriately selecteddepending on the purpose, but is preferably the following method forproducing the compound of the present invention.

<Method for Producing Compound Represented by General Formula (1)>

The method for producing the compound of the present invention is amethod for producing the compound represented by the general formula(1), the method including a reaction step of reacting together acompound represented by the following general formula (2), a compoundrepresented by the following general formula (3), and a compoundrepresented by the following general formula (4), and further includingother steps if necessary.

In the general formula (2), R¹ represents any of a protective group of acarboxyl group, and a hydrogen atom. In the general formula (3), R² andR³ each independently represent any of a protective group of an aminogroup, and a hydrogen atom. In the general formula (4), R⁴ representsany of a protective group of a carboxyl group, and a hydrogen atom.

R¹ in the general formula (2) is the same as R¹ in the general formula(1). Preferable aspects thereof are also the same as those of R¹ in thegeneral formula (1).

R² and R³ in the general formula (3) are the same as R² and R³ in thegeneral formula (1), respectively. Preferable aspects thereof are alsothe same as those of R² and R³ in the general formula (1).

R⁴ in the general formula (4) is the same as R⁴ in the general formula(1). Preferable aspects thereof are also the same as those of R⁴ in thegeneral formula (1).

—Reaction Step—

The reaction step is not particularly limited and can be appropriatelyselected depending on the purpose, but is preferably performed using acatalyst.

In addition, the reaction step is preferably performed by a catalyticasymmetric reaction.

The catalyst is preferably a copper complex. As the copper complex, acopper complex of copper bromide (I) and a ligand is preferable.

The ligand is not particularly limited and can be appropriately selecteddepending on the purpose, and examples thereof include a pyridinebisoxazoline ligand. Examples of the pyridine bisoxazoline ligandinclude a compound represented by the following general formula (A).

In the general formula (A), R¹, R², and R³ each independently representany of a hydrogen atom, an alkyl group, an alkenyl group, an aryl group,and an aralkyl group, and R⁴ represents any of a hydrogen atom, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkylgroup, an alkenyl group, an aryl group, an aralkyl group, an oxygenatom, a sulfur atom, and a nitrogen atom (wherein an oxygen atom, asulfur atom, and a nitrogen atom have any of a hydrogen atom and asubstituent). It is to be noted that the alkyl group, the alkenyl group,the aryl group, and the aralkyl group may have a substituent.

The alkyl group is not particularly limited and can be appropriatelyselected depending on the purpose, and examples thereof include an alkylgroup having 1 to carbon atoms. Examples of the alkyl group having 1 to10 carbon atoms include a methyl group, an ethyl group, a propyl group,an i-propyl group, and a t-butyl group.

The alkenyl group is not particularly limited and can be appropriatelyselected depending on the purpose, and examples thereof include analkenyl group having 2 to 10 carbon atoms. Examples of the alkenyl grouphaving 2 to 10 carbon atoms include a vinyl group and a 1-propenylgroup.

The aryl group is not particularly limited and can be appropriatelyselected depending on the purpose, and examples thereof include an arylgroup having 4 to 14 carbon atoms in a backbone portion. Examples of thebackbone portion include a phenyl group and a naphthyl group. Amongthem, a phenyl group is preferable as the backbone portion.

The aralkyl group (arylalkyl group) is not particularly limited, and canbe appropriately selected depending on the purpose.

The compound represented by the general formula (A) is preferably(S,S)-2,6-bis(4,5-dihydro-4-phenyl-2-oxazolyl)pyridine ((S)-ph-pybox)represented by the following structure. Using such an optically-activeligand enable a catalytic asymmetric synthesis.

The catalyst is preferably a combination of copper bromide (I) and(S,S)-2,6-bis(4,5-dihydro-4-phenyl-2-oxazolyl)pyridine ((S)-ph-pybox) interms of production yield and optical yield.

The amount of the catalyst to be used in the reaction step is notparticularly limited and can be appropriately selected depending on thepurpose, but is preferably 1% by mole to 5% by mole with respect to thatof the compound represented by the general formula (2).

A solvent for use in the reaction step is not particularly limited andcan be appropriately selected depending on the purpose, and examplesthereof include toluene, THF (tetrahydrofuran), and ethyl acetate.

The reaction temperature in the reaction step is not particularlylimited and can be appropriately selected depending on the purpose, butis preferably 0° C. to 25° C.

The reaction time in the reaction step is not particularly limited andcan be appropriately selected depending on the purpose, but ispreferably 3 hours to 12 hours.

The pressure in the reaction step is not particularly limited and can beappropriately selected depending on the purpose, but is preferablyatmosphere pressure.

There may be a case where the compound represented by the generalformula (1) of the present invention is obtained as a mixture ofstereoisomers, and such a case is also encompassed within the scope ofthe present invention. Preferable is an optically active form (S-formexcess).

The compound represented by the general formula (1) of the presentinvention is useful as an intermediate for industrially producingoseltamivir phosphate.

(Compound Represented by General Formula (5) and Method for ProducingSame) <Compound Represented by General Formula (5)>

The compound of the present invention is a compound represented by thefollowing general formula (5).

In the general formula (5), R¹ represents any of a protective group of acarboxyl group, and a hydrogen atom, R² and R³ each independentlyrepresent any of a protective group of an amino group, and a hydrogenatom, and R⁴ represents any of a protective group of a carboxyl group,and a hydrogen atom.

Specific examples of R¹, R², R³, and R⁴ in the general formula (5)include those recited as the specific examples of R¹, R², R³, and R⁴ inthe general formula (1), respectively. Preferable aspects thereof arealso the same as those of R¹, R², R³, and R⁴ in the general formula (1),respectively.

The method for producing the compound represented by the general formula(5) is not particularly limited and can be appropriately selecteddepending on the purpose, but is preferably the following method forproducing the compound of the present invention.

<Method for Producing Compound Represented by General Formula (5)>

The method for producing the compound of the present invention is amethod for producing the compound represented by the following generalformula (5), the method including a reduction step of reducing a triplebond of the compound represented by the general formula (1) to a doublebond, and further including other steps if necessary.

—Reduction Step—

The reduction step is not particularly limited and can be appropriatelyselected depending on the purpose, and examples thereof include a stepof using a reducing agent.

The reducing agent is not particularly limited and can be appropriatelyselected depending on the purpose, but is preferablytetramethyldisiloxane.

In addition, a catalyst is preferably used in the reduction step. Thecatalyst is not particularly limited and can be appropriately selecteddepending on the purpose, but is preferably a palladium compound.Examples of the palladium compound include divalent palladium compoundssuch as palladium acetate and zerovalent palladium compounds such astris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃).

A solvent for use in the reduction step is not particularly limited andcan be appropriately selected depending on the purpose, and examplesthereof include toluene, THF (tetrahydrofuran), and DMF(N,N-dimethylformamide).

The reaction temperature in the reduction step is not particularlylimited and can be appropriately selected depending on the purpose, butis preferably 40° C. to 60° C.

The reaction time in the reduction step is not particularly limited andcan be appropriately selected depending on the purpose, but ispreferably 12 hours to 24 hours.

There may be a case where the compound represented by the generalformula (5) of the present invention is obtained as a mixture ofstereoisomers, and such a case is also encompassed within the scope ofthe present invention. Preferable is an optically active form (S-formexcess).

The compound represented by the general formula (5) of the presentinvention is useful as an intermediate for industrially producingoseltamivir phosphate.

(Compound Represented by General Formula (6) and Method for ProducingSame) <Compound Represented by General Formula (6)>

The compound of the present invention is a compound represented by thefollowing general formula (6).

In the general formula (6), R¹ represents any of a protective group of acarboxyl group, and a hydrogen atom, and R² and R³ each independentlyrepresent any of a protective group of an amino group, and a hydrogenatom.

It is to be noted that the compound represented by the general formula(6) is a keto-enol tautomer.

Specific examples of R¹, R², and R³ in the general formula (6) includethose recited as the specific examples of R¹, R², and R³ in the generalformula (1), respectively. Preferable aspects thereof are also the sameas those of R¹, R², and R³ in the general formula (1), respectively.

The method for producing the compound represented by the general formula(6) is not particularly limited and can be appropriately selecteddepending on the purpose, but is preferably the following method forproducing the compound of the present invention.

<Method for Producing Compound Represented by General Formula (6)>

The method for producing the compound of the present invention is amethod for producing the compound represented by the general formula(6), the method including a cyclization step of cyclizing the compoundrepresented by the general formula (5), and further including othersteps if necessary.

—Cyclization Step—

The cyclization step is not particularly limited, can be appropriatelyselected depending on the purpose, and can be performed by Dieckmanncyclization.

In the Dieckmann cyclization, a reaction can be performed under mildconditions, and lithium hexamethyldisilazide is preferably used thereforbecause of having a high reaction rate. For example, if potassiumtert-butoxide (KOt-Bu) is used, a by-product may be produced, and ifsodium hydride is used, the reaction does not progress.

A solvent for use in the cyclization step is not particularly limitedand can be appropriately selected depending on the purpose, and examplesthereof include toluene, THF (tetrahydrofuran), and DMF(N,N-dimethylformamide).

The reaction temperature in the cyclization step is not particularlylimited and can be appropriately selected depending on the purpose, butis preferably −40° C. to −20° C.

The reaction time in the cyclization step is not particularly limitedand can be appropriately selected depending on the purpose, but ispreferably 30 minutes to 2 hours.

There may be a case where the compound represented by the generalformula (6) of the present invention is obtained as a mixture ofstereoisomers, and such a case is also encompassed within the scope ofthe present invention. Preferable is an optically active form (S-formexcess).

The compound represented by the general formula (6) of the presentinvention is useful as an intermediate for industrially producingoseltamivir phosphate.

(Compound Represented by General Formula (7) and Method for ProducingSame) <Compound Represented by General Formula (7)>

The compound of the present invention is a compound represented by thefollowing general formula (7).

In the general formula (7), R¹ represents any of a protective group of acarboxyl group, and a hydrogen atom, and R² and R³ each independentlyrepresent any of a protective group of an amino group, and a hydrogenatom.

Specific examples of R¹, R², and R³ in the general formula (7) includethose recited as the specific examples of R¹, R², and R³ in the generalformula (1), respectively. Preferable aspects thereof are also the sameas those of R¹, R², and R³ in the general formula (1), respectively.

The method for producing the compound represented by the general formula(7) is not particularly limited and can be appropriately selecteddepending on the purpose, but is preferably the following method forproducing the compound of the present invention.

<Method for Producing Compound Represented by General Formula (7)>

The method for producing the compound of the present invention is amethod for producing a compound represented by the general formula (7),the method including a reduction step of reducing a carbonyl group ofthe compound represented by the general formula (6) to a hydroxyl group,and further including other steps if necessary.

—Reduction Step—

The reduction step is not particularly limited and can be appropriatelyselected depending on the purpose, and examples thereof include a stepof using a reducing agent such as LiAlH₄ or NaBH₄. In the case whereNaBH₄ is used, reduction is usually performed in the presence of analcohol such as methanol or ethanol.

A solvent for use in the reduction step is not particularly limited andcan be appropriately selected depending on the purpose, and examplesthereof include methanol, ethanol, toluene, THF (tetrahydrofuran), andDMF (N,N-dimethylformamide).

The reaction temperature in the reduction step is not particularlylimited and can be appropriately selected depending on the purpose, butis preferably −40° C. to 0° C.

The reaction time in the reduction step is not particularly limited andcan be appropriately selected depending on the purpose, but ispreferably 30 minutes to 2 hours.

There may be a case where the compound represented by the generalformula (7) of the present invention is obtained as a mixture ofstereoisomers, and such a case is also encompassed within the scope ofthe present invention. Preferable is an optically active form (S-formexcess).

The compound represented by the general formula (7) of the presentinvention is useful as an intermediate for industrially producingoseltamivir phosphate.

(Compound Represented by General Formula (8) and Method for ProducingSame) <Compound Represented by General Formula (8)>

The compound of the present invention is a compound represented by thefollowing general formula (8).

In the general formula (8), R¹ represents any of a protective group of acarboxyl group, and a hydrogen atom, and R⁵ represents any of aprotective group of an amino group, and a hydrogen atom.

Specific examples of R¹ in the general formula (8) include those recitedas the specific examples of R¹ in the general formula (1). Preferableaspects thereof are also the same as those of R¹ in the general formula(1).

The protective group of an amino group in R⁵ in the general formula (8)is not particularly limited and can be appropriately selected dependingon the purpose, and examples thereof include the protective groups of anamino group recited in the description of R² and R³ in the generalformula (1). Among them, a tert-butoxycarbonyl group is preferable inthat the subsequent deprotection thereof is easy.

The method for producing the compound represented by the general formula(8) is not particularly limited and can be appropriately selecteddepending on the purpose, but is preferably the following method forproducing the compound of the present invention.

<Method for Producing Compound Represented by General Formula (8)>

The method for producing the compound of the present invention is amethod for producing the compound represented by the general formula(8), the method including a conversion step of converting an NR²R³ groupof the compound represented by the general formula (7) to an NHR⁵ groupwherein R⁵ is a protective group of an amino group, and the protectivegroup R⁵ is different from R² and R³, and further including other stepsif necessary.

—Conversion Step—

The conversion step is not particularly limited and can be appropriatelyselected depending on the purpose, and examples thereof include a stepof deprotecting R² and R³ and then adding R⁵ being a protective group.

A solvent for use in the conversion step is not particularly limited andcan be appropriately selected depending on the purpose, and examplesthereof include methylene chloride, methanol, ethanol, toluene, THF(tetrahydrofuran), and DMF (N,N-dimethylformamide).

The reaction temperature in the conversion step is not particularlylimited and can be appropriately selected depending on the purpose, butis preferably 0° C. to 40° C.

The reaction time in the conversion step is not particularly limited andcan be appropriately selected depending on the purpose, but ispreferably 2 hours to 8 hours.

In the case where R² and R³ are each an allyl group and R⁵ is atert-butoxycarbonyl group, for example, preferable is a step ofdeprotecting allyl groups of R² and R³ by usingtetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄) andN,N-dimethylbarbituric acid, and then adding a tert-butoxycarbonyl groupas R⁵ by using di-tert-butyl dicarbonate.

There may be a case where the compound represented by the generalformula (8) is obtained as a mixture of stereoisomers, and such a caseis also encompassed within the scope of the present invention. Herein,the compound is not a racemic form but an optically active form (S-formexcess).

The compound represented by the general formula (8) of the presentinvention is useful as an intermediate for industrially producingoseltamivir phosphate.

(Method for Producing Compound Represented by General Formula (9))<First Production Method>

The method for producing the compound of the present invention (firstproduction method) is a method for producing a compound represented bythe following general formula (9), the method including a dehydrationstep of dehydrating the compound represented by the general formula (8)by a dehydration reaction, and further including other steps ifnecessary.

In the general formula (9), R¹ represents any of a protective group of acarboxyl group, and a hydrogen atom, and R⁵ represents any of aprotective group of an amino group, and a hydrogen atom.

Specific examples of R¹ in the general formula (9) include those recitedas the specific examples of R¹ in the general formula (1). Preferableaspects thereof are also the same as those of R¹ in the general formula(1).

Specific examples of R⁵ in the general formula (9) include those recitedas the specific examples of R⁵ in the general formula (8). Preferableaspects thereof are also the same as those of R⁵ in the general formula(8).

The reaction temperature in the dehydration step is not particularlylimited and can be appropriately selected depending on the purpose, butis preferably −20° C. to 40° C. and more preferably −2° C. to 30° C.

The reaction time in the dehydration step is not particularly limitedand can be appropriately selected depending on the purpose, but ispreferably 30 minutes to 5 hours and more preferably 1.5 hours to 3hours.

In the dehydration step, a base is preferably used. The base is notparticularly limited and can be appropriately selected depending on thepurpose, but is preferably a diazabicyclo compound.

Examples of the diazabicyclo compound include1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]nonene-5 (DBN), and1,4-diazabicyclo[2.2.2]octane. Among them,1,8-diazabicyclo[5.4.0]undec-7-ene is preferable in that it isinexpensively available.

In the dehydration step, the diazabicyclo compound and a tertiary amineare preferably used in combination. Using the diazabicyclo compound andthe tertiary amine in combination makes it possible to provide thecompound represented by the general formula (9) at a high yield.

The tertiary amine is not particularly limited and can be appropriatelyselected depending on the purpose, and examples thereof includetrialkylamine, triallylamine, tetramethylethylenediamine,triethylenediamine, N-methylmorpholine,4,4′-(oxydi-2,1-ethanediyl)bismorpholine, N,N-dimethylbenzylamine,pyridine, picoline, dimethylaminomethyl phenol, trisdimethylaminomethylphenol, triethanolamine, N,N′-dimethylpiperazine,tetramethylbutanediamine, bis(2,2-morpholinoethyl)ether, andbis(dimethylaminoethyl)ether.

Examples of the trialkylamine include trimethylamine, triethylamine,tripropylamine, tributylamine, triamylamine, trihexylamine,trioctylamine, trilaurylamine, dimethylethylamine, dimethylpropylamine,dimethylbutylamine, dimethylamylamine, dimethylhexylamine,dimethylcyclohexylamine, dimethyloctylamine, and dimethyllaurylamine.

Among them, trialkylamine is preferable and triethylamine is morepreferable in that they have the highest versatility and are easilyavailable.

The amount of the diazabicyclo compound to be added in the dehydrationstep is not particularly limited and can be appropriately selecteddepending on the purpose, but is preferably 0.5 mol to 10 mol and morepreferably 2 mol to 5 mol with respect to 1 mol of the compoundrepresented by the general formula (8). If the amount to be added isless than 0.5 mol, the reaction rate may be reduced, and if it exceeds10 mol, degradation of a substrate may occur. If the amount to be addedis within the more preferable range, there is an advantage of excellentreaction rate.

The amount of the tertiary amine to be added in the dehydration step isnot particularly limited and can be appropriately selected depending onthe purpose, but is preferably 0.5 mol to 10 mol and more preferably 2mol to 5 mol with respect to 1 mol of the compound represented by thegeneral formula (8). If the amount to be added is less than 0.5 mol, thereaction rate may be reduced, and if it exceeds 10 mol, a by-product maybe generated. If the amount to be added is within the more preferablerange, there is an advantage of excellent reaction rate.

<Second Production Method>

The method for producing the compound of the present invention (secondproduction method) is a method for producing the compound represented bythe general formula (9), the method including:

reacting together the compound represented by the general formula (2),the compound represented by the general formula (3), and the compoundrepresented by the general formula (4) to provide the compoundrepresented by the general formula (1);

reducing a triple bond of the compound represented by the generalformula (1) to a double bond to provide the compound represented by thegeneral formula (5);

cyclizing the compound represented by the general formula (5) to providethe compound represented by the general formula (6);

reducing a carbonyl group of the compound represented by the generalformula (6) to a hydroxyl group to provide the compound represented bythe general formula (7);

converting an NR²R³ group of the compound represented by the generalformula (7) to an NHR⁵ group, wherein R⁵ is a protective group of anamino group and the protective group R⁵ is different from R² and R³, toprovide the compound represented by the general formula (8); and

dehydrating the compound represented by the general formula (8) by adehydration reaction to provide the compound represented by the generalformula (9); and

further including other steps if necessary.

The respective steps in the production method are the same as therespective steps in the production method of the present inventiondescribed above.

That is, the step of providing the compound represented by the generalformula (1) is the same as the step described in the method forproducing the compound represented by the general formula (1) of thepresent invention. Preferable aspects thereof are also ditto.

The step of providing the compound represented by the general formula(5) is the same as the reduction step in the method for producing thecompound represented by the general formula (5) of the presentinvention. Preferable aspects thereof are also ditto.

The step of providing the compound represented by the general formula(6) is the same as the cyclization step in the method for producing thecompound represented by the general formula (6) of the presentinvention. Preferable aspects thereof are also ditto.

The step of providing the compound represented by the general formula(7) is the same as the reduction step in the method for producing thecompound represented by the general formula (7) of the presentinvention. Preferable aspects thereof are also ditto.

The step of providing the compound represented by the general formula(8) is the same as the conversion step in the method for producing thecompound represented by the general formula (8) of the presentinvention. Preferable aspects thereof are also ditto.

The step of providing the compound represented by the general formula(9) is the same as the dehydration step in the method for producing thecompound represented by the general formula (9) of the present invention(first production method). Preferable aspects thereof are also ditto.

(Method for Producing Oseltamivir Phosphate)

The method for producing oseltamivir phosphate of the present inventionincludes: the method for producing the compound represented by thegeneral formula (1), the method for producing the compound representedby the general formula (5), the method for producing the compoundrepresented by the general formula (6), the method for producing thecompound represented by the general formula (7), the method forproducing the compound represented by the general formula (8), or themethod for producing the compound represented by the general formula(9), or any combination thereof; and further includes other steps ifnecessary.

The oseltamivir phosphate is known as a trade name “Tamiflu,” and is acompound represented by the following structure.

<Other Steps>

The aforementioned other steps include a step of using the compoundrepresented by the general formula (9) to synthesize the oseltamivirphosphate. Such a step is not particularly limited and can beappropriately selected depending on the purpose, and examples thereofinclude a step described in J. Am. Chem. Soc., 128, 6310, 2006. Oneexample of this step includes a step represented by the followingsynthesis scheme.

In the synthesis scheme, “Et” represents an “ethyl group.” “Boc” and“t-Boc” represent a “tert-butoxycarbonyl group.” “NBA” represents“N-bromoacetamide.” “Ac” represents an “acetyl group.” “KHMDS”represents “potassium hexamethyldisilazide.” “^(n)Bu” represents a“n-butyl group.” “DME” represents “dimethoxyethane.” “TFA” represents“trifluoroacetic acid.” The numeral values in parentheses of “NBA,”“KHMDS,” and “^(n)Bu₄NBr” represent an amount in equivalents.

It is to be noted that the reaction conditions and reagents shown in thesynthesis scheme are examples, and the reaction in the step are notlimited by these specific conditions and reagents.

EXAMPLES

Hereinafter, the present invention will be specifically described withreference to Examples, but the present invention is not limited to theseExamples at all.

In Examples, “Me”” represents a “methyl group.” “Et” represents an“ethyl group.” “Boc” represents a “tert-butoxycarbonyl group.”

Example 1 Synthesis of Compound 1-1

Monovalent copper bromide (available from Wako Chemical, Ltd., 2.9 mg,0.0200 mmol, 5% by mole) and the following ligand A-1 (available fromSigma-Aldrich Co. LLC, 8.1 mg, 0.0220 mmol, 5.5% by mole) were chargedto a well-dried test tube, and toluene (1.6 mL) was added thereto understirring at room temperature. After stirring at room temperature for 30minutes, a molecular sieve 4A (MS4A, 240 mg), the following compound 4-1(available from Wako Chemical, Ltd., 0.0811 mL, 0.800 mmol, 2equivalents), the following compound 2-1 (0.0500 mL, 0.400 mmol, 1equivalent, synthesized according to Coffin, B.; Robbins, R. F. J. Chem.Soc. C 1996, 334.), and the following compound 3-1 (available from TokyoChemical Industry Co., Ltd., 0.0988 mL, 0.800 mmol, 2 equivalents) weresequentially added thereto, and stirred at room temperature for 14hours. Subsequently, the resultant was subjected to filtration andconcentration, and also to silica gel purification (hexane/ethylacetate=8/1 to 6/1 (volume ratio)), thereby providing the followingcompound 1-1 (109.9 mg, 0.358 mmol, yield: 89%, 43% e.e.).

The Rf (Relative to Front) value, ¹H NMR spectrum, ¹³C NMR spectrum, IRspectrum, ESI-MS spectrum, ESI-HRMS spectrum, specific optical rotation,and HPLC data of the obtained compound 1-1 are shown below.

Rf value: 0.3 (hexane/ethyl acetate=6/1 (volume ratio))

¹H NMR (CDCl₃, 400 MHz): δ 5.73 (m, 2H), 5.21 (d, J=17.0 Hz, 2H), 5.11(d, J=10.5 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.71(dd, J=7.8 Hz, 7.1 Hz, 1H), 3.28 (m, 2H), 2.87 (dd, J=14.0 Hz, 7.8 Hz,2H), 2.42 (m, 2H), 1.99 (m, 2H), 1.30 (t, J=7.1 Hz, 3H), 1.24 (t, J=7.0Hz, 3H)

¹³C NMR (CDCl₃, 100 MHz) δ 172.9, 153.6, 135.9, 117.7, 85.9, 77.6, 62.0,60.5, 53.7, 51.3, 30.9, 27.9, 14.3, 14.0

IR (neat, cm⁻¹) 3081, 2981, 2819, 2225, 1740, 1712

ESI-MS m/z 330.2 [M+Na]⁺

ESI-HRMS Calcd for C₁₇H₂₅NO₄Na [M+Na]⁺: 330.1676. Found: 330.1674[α]_(D) ²²=−40.1 (34% ee, c=0.97, CHCl₃)

HPLC (hexane/isopropanol=50/1 (volume ratio), CHIRALPAK IC, 0.5 mL/min,254 nm) t_(R)=17.8 min (minor), 19.6 min (major).

Example 2 Synthesis of Compound 1-2

The same synthesis procedure as in Example 1 was performed except thatthe compound 3-1 in Example 1 was replaced to the following compound 3-2(synthesized according to Anastasi, C.; Hantz, O.; Clercq, E. D.;Pannecouque, C.; Clayette, P.; Dereuddre-Bosquet, N.; Dormont, D.;Gondois-Rey, F.; Hirsch, I.; Kraus, J.-L. J. Med. Chem. 2004, 47,1183.), thereby providing the following compound 1-2 (yield: 83%, 25%e.e.).

The Rf (Relative to Front) value, ¹H NMR spectrum, ¹³C NMR spectrum, IRspectrum, ESI-MS spectrum, ESI-HRMS spectrum, specific optical rotation,and HPLC data of the obtained compound 1-2 are shown below.

Rf value: 0.55 (hexane/ethyl acetate=2/1 (volume ratio))

¹H NMR (CDCl₃, 400 MHz): δ 7.16 (d, J=8.7 Hz, 4H), 6.76 (d, J=8.7 Hz,4H), 4.20 (q, J=7.1 Hz, 2H), 3.93 (q, J=7.2 Hz, 2H), 3.72-3.68 (m, 8H),3.49 (dd, J=8.5 Hz, 6.9 Hz, 1H), 3.23 (d, J=13.3 Hz, 2H), 2.37-2.23 (m,2H), 1.97-1.93 (m, 2H), 1.27 (t, J=7.1 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H)

¹³C NMR (CDCl₃, 100 MHz): δ 172.7, 158.9, 153.7, 130.8, 130.0, 113.8,85.8, 77.8, 62.1, 60.5, 55.3, 54.1, 50.6, 30.8, 27.7, 14.2, 14.2

IR (neat, cm⁻²) 2981, 2834, 2221, 1731, 1712

ESI-MS m/z 490.2 [M+Na]⁺

ESI-HRMS Calcd for C₂₁H₃₃NO₆Na [M+Na]⁺: 490.2200. Found: 490.2197

[α]_(D)23=−37.9 (25% ee, c=1.05, CHCl₃)

HPLC (hexane/isopropanol=50/1 (volume ratio), CHIRALPAK IC, 1.0 mL/min,254 nm) t_(R)=39.7 min (minor), 50.0 min (major).

Example 3 Synthesis of Compound 1-3

The same synthesis procedure as in Example 1 was performed except thatthe compound 3-1 in Example 1 was replaced to the following compound 3-3(synthesized according to Lee, O.-Y.; Law, K.-L.; Yang, D. Org. Lett.2009, 11, 3302), thereby providing the following compound 1-3 (yield:82%, 35% e.e.).

The Rf (Relative to Front) value, ¹H NMR spectrum, ¹³C NMR spectrum, IRspectrum, ESI-MS spectrum, ESI-HRMS spectrum, specific optical rotation,and HPLC data of the obtained compound 1-3 are shown below.

Rf value: 0.5 (hexane/ethyl acetate=4/1 (volume ratio))

¹H NMR (CDCl₃, 400 MHz): δ 7.25 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz,2H), 5.79 (m, 1H), 5.28 (d, J=17.2 Hz, 1H), 5.16 (d, J=10.1 Hz, 1H),4.28 (q, J=7.1 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.85 (d, J=13.5 Hz, 1H),3.81 (s, 3H), 3.66 (dd, J=8.5 Hz, 7.1 Hz, 1H), 3.33-3.28 (m, 2H), 2.94(dd, J=14.4, 8.2 Hz, 1H), 2.42 (m, 2H), 2.02 (m, 2H), 1.36 (t, J=7.1 Hz,3H), 1.26 (t, J=7.1 Hz, 3H)

¹³C NMR (CDCl₃, 100 MHz): δ 172.8, 158.8, 153.6, 136.0, 130.8, 130.0,117.8, 113.8, 85.9, 77.7, 62.1, 60.5, 55.3, 54.3, 53.5, 51.0, 30.8,27.8, 14.3, 14.1

IR (neat, cm⁻¹) 2981, 2834, 2221, 1731, 1712

ESI-MS m/z 410.3 [M+Na]⁺

ESI-HRMS Calcd for C₂₂H₂₉NO₅Na [M+Na]⁺: 410.1938. Found: 410.1935

[α]_(D) ²²=−58.0 (35% ee, c=0.95, CHCl₃)

HPLC (hexane/isopropanol=50/1 (volume ratio), CHIRALPAK IC, 1.0 mL/min,254 nm) t_(R)=16.9 min (minor), 19.3 min (major).

Example 4 Synthesis of Compound 1-4

The same synthesis procedure as in Example 1 was performed except thatthe compound 4-1 in Example 1 was replaced to the following compound 4-4(available from Wako Chemical, Ltd.), thereby providing the followingcompound 1-4 (yield: 89%, 41% e.e.).

The Rf (Relative to Front) value, ¹H NMR spectrum, ¹³C NMR spectrum, IRspectrum, ESI-MS spectrum, ESI-HRMS spectrum, specific optical rotation,and HPLC data of the obtained compound 1-4 are shown below.

Rf value: 0.3 (hexane/ethyl acetate=6/1 (volume ratio))

¹H NMR (CDCl₃, 400 MHz): δ 5.72 (m, 2H), 5.20 (d, J=17.0 Hz, 2H), 5.11(d, J=10.5 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.70 (m, 4H), 3.27 (m, 2H),2.87 (dd, J=14.0 Hz, 7.8 Hz, 2H), 2.41 (m, 2H), 2.00 (m, 2H), 1.24 (t,J=7.0 Hz, 3H)

¹³C NMR (CDCl₃, 100 MHz): δ 172.6, 153.8, 135.9, 117.6, 85.7, 77.6,60.5, 53.5, 52.5, 51.5, 30.9, 28.0, 14.0

IR (neat, cm⁻¹) 3080, 2980, 2819, 2222, 1742, 1713

ESI-MS m/z 316.2 [M+Na]⁺

ESI-HRMS Calcd for C₁₆H₂₃NO₄Na [M+Na]⁺: 316.1519. Found: 316.1518[α]_(D) ²³=−52.3 (41% ee, c=0.98, CHCl₃)

HPLC (hexane/isopropanol=50/1 (volume ratio), CHIRALPAK IC, 0.5 mL/min,254 nm) t_(R)=18.2 min (minor), 20.1 min (major).

Example 5 Synthesis of Compound 5-1

To Pd₂(dba)₃.CHCl₃ (available from Sigma-Aldrich Co. LLC, chloroformadduct of tris(dibenzylideneacetone)dipalladium (0), 105 mg, 0.102 mmol,2.5% by mole) and tris(2-methylphenyl)phosphine (available from TokyoChemical Industry Co., Ltd., P (o-tol)₃, 124 mg, 0.406 mmol, 10% bymole) dissolved in toluene (10.3 mL) were sequentially added1,1,3,3-tetramethyldisiloxane (available from Tokyo Chemical IndustryCo., Ltd., Me₂HSiOSiHMe₂, 0.718 mL, 4.06 mmol, 1 equivalent), aceticacid (AcOH, 0.232 mL, 4.06 mmol, 1 equivalent), and a solution of thecompound 1-1 synthesized in Example 1 in toluene (0.406 M, 10 mL, 4.06mmol, 1 equivalent) at room temperature, and stirred at 45° C. for 19hours. After the resultant was cooled to room temperature, ethyl acetateand an aqueous saturated sodium hydrogen carbonate solution were addedthereto. The aqueous layer was extracted with ethyl acetate, and theorganic layer was washed with saturated saline and then dried withsodium sulfate, and then subjected to distillation off of the solventand silica gel purification (hexane/ethyl acetate=9/1 to 7/1 (volumeratio)), thereby providing the following compound 5-1 (450 mg, 1.45mmol) at a yield of 36%.

The Rf (Relative to Front) value, ¹H NMR spectrum, ¹³C NMR spectrum, IRspectrum, ESI-MS spectrum, ESI-HRMS spectrum, and specific opticalrotation of the obtained compound 5-1 are shown below.

Rf value: 0.3 (hexane/ethyl acetate=4/1 (volume ratio))

¹H NMR(CDCl₃, 400 MHz): δ 6.12 (dd, J=11.4 Hz, 10.3 Hz, 1H), 5.89 (d,J=11.4 Hz, 1H), 5.80-5.70 (m, 2H), 5.13-5.04 (m, 4H), 4.45 (m, 1H),4.15-4.07 (m, 4H), 3.26 (m, 2H), 2.91 (dd, J=14.4 Hz, 7.4 Hz, 2H), 2.46(m, 1H), 2.30 (m, 1H), 1.93 (m, 1H), 1.73 (m, 1H), 1.28-1.21 (m, 6H)

¹³C NMR (CDCl₃, 100 MHz): δ 173.7, 165.8, 147.4, 136.6, 122.1, 116.7,60.2, 60.2, 56.1, 52.6, 31.1, 27.4, 14.3, 14.3

IR (neat, cm⁻¹) 3077, 2981, 2811, 1720

ESI-MS m/z 332.2 [M+Na]⁺

ESI-HRMS Calcd for C₁₇H₂₅NO₄ [M+H]⁺: 310.2013. Found: 310.2010

[α]_(D) ²²=44.2 (34% ee, c=0.90, CHCl₃).

Example 6 Synthesis of Compound 6-1

The compound 5-1 obtained in Example 5 (340 mg, 1.10 mmol) was dissolvedin THF (tetrahydrofuran, 5.49 mL), and a solution of lithiumhexamethyldisilazide

(LHMDS) in THF (1.0 M, 3.30 mL, 3.30 mmol, 3 equivalents) was slowlyadded thereto at −40° C. and stirred for 30 minutes. After the resultantwas diluted with ethyl acetate, an aqueous saturated ammonium chloridesolution was added thereto, and the aqueous layer was extracted withethyl acetate. The organic layer was washed with saturated saline anddried with sodium sulfate, and then the solvent was distilled off,thereby providing the following compound 6-1 (314 mg) as a keto-enolmixture. The obtained crude product was used in the next reaction as itwas.

The Rf (Relative to Front) value, IR spectrum, ESI-MS spectrum, andESI-HRMS spectrum of the obtained compound 6-1 are shown below.

Rf value: 0.2 (hexane/ethyl acetate=4/1 (volume ratio))

IR (neat, cm⁻¹) 2981, 2815, 1739, 1685

ESI-MS m/z 286.1 [M+Na]⁺ ESI-HRMS Calcd for C₁₅H₂₂NO₃ [M+H]⁺: 264.1594.Found: 264.1592.

The ¹H NMR spectrum is shown in FIG. 2.

Example 7 Synthesis of Compound 7-1

The compound 6-1 obtained in Example 6 (crude product, 312 mg) wasdissolved in methanol (MeOH, 5.49 mL), and sodium borohydride (NaBH₄,83.2 mg, 2.20 mmol) was added thereto at −20° C. and stirred for 30minutes. An aqueous saturated ammonium chloride solution was addedthereto, and thereafter, methanol was distilled off under reducedpressure. Ethyl acetate was further added thereto, and the producedaqueous layer was extracted with ethyl acetate. The organic layer waswashed with saturated saline and dried with sodium sulfate, and thensubjected to distillation off of the solvent and silica gel purification(hexane/ethyl acetate=2/1 (volume ratio)), thereby providing thefollowing compound 7-1 (180 mg, 0.680 mmol) as a diastereomer mixture ata yield of 62%.

The Rf (Relative to Front) value, IR spectrum, ESI-MS spectrum, andESI-HRMS spectrum of the obtained compound 7-1 are shown below.

Rf value: 0.1 (hexane/ethyl acetate=4/1 (volume ratio))

IR (neat, cm⁻¹) 2978, 2811, 1731

ESI-MS m/z 288.2 [M+Na]⁺

ESI-HRMS Calcd for C₁₅H₂₁NO₃ [M+H]⁺: 266.1751. Found: 266.1750.

The ¹H NMR spectrum is shown in FIG. 3.

Example 8 Synthesis of Compound 8-1

The compound 7-1 synthesized in Example 7 (180 mg, 0.680 mmol) wasdissolved in methylene chloride (3.39 mL), and Pd(PPh₃)₄ (available fromTokyo Chemical Industry Co., Ltd., tetrakis(triphenylphosphine)palladium(0), 78.4 mg, 0.0678 mmol, 10% by mole) and N,N-dimethylbarbituric acid(636 mg, 4.07 mmol, 6 equivalents) were sequentially added thereto atroom temperature and then stirred for 1 hour. The solvent was distilledoff, and a solution of Boc₂O (di-tert-butyl dicarbonate) in acetonitrile(0.82 M, 4.13 mL, 3.39 mmol, 5 equivalents) and an aqueous saturatedsodium hydrogen carbonate solution (3.39 mL) were sequentially addedthereto and stirred at room temperature for 3 hours. After the resultantwas diluted with ethyl acetate, an aqueous saturated sodium hydrogencarbonate solution was added thereto and the aqueous layer was extractedwith ethyl acetate. The organic layer was washed with saturated saline,dried with sodium sulfate, and then subjected to distillation off of thesolvent and silica gel purification (hexane/ethyl acetate=1/1 (volumeratio)), thereby providing the following compound 8-1 (175 mg, 0.613mmol) as a diastereomer mixture at a yield of 91%.

The Rf (Relative to Front) value, IR epectrum, ESI-MS spectrum, andESI-HRMS spectrum of the obtained compound 8-1 are shown below.

Rf value: 0.15 (hexane/ethyl acetate=2/1 (volume ratio))

IR (neat, cm⁻¹) 3367, 2977, 1689

ESI-MS m/z 308.1 [M+Na]⁺

ESI-HRMS Calcd for C₁₄H₂₃NO₅Na [M+Na]⁺: 308.1468. Found: 308.1468.

The ¹H NMR spectrum is shown in FIG. 4.

The result that the compound 9-1 obtained in Example 9 hereafter is anoptically active form of the S-form excess confirms that the obtainedcompound 8-1 is also an optically active form of the S-form excess.

Example 9 Synthesis of Compound 9-1

The compound 8-1 obtained in Example 8 (172 mg, 0.603 mmol) wasdissolved in methylene chloride (3.01 mL), methanesulfonyl chloride(0.0513 mL, 0.663 mmol, 1.1 equivalents) and triethylamine (0.167 mL,1.21 mmol, 2 equivalents) were sequentially added thereto under coolingin ice and stirred for 10 minutes, and thereafter1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.279 mL, 1.87 mmol, 3.1equivalents) was further added thereto and stirred at 25° C. for 1 hour.After the resultant was diluted with methylene chloride and water, theaqueous layer was extracted with methylene chloride. The organic layerwas sequentially washed with an aqueous 1 N hydrochloric acid solution,an aqueous saturated sodium hydrogen carbonate solution and saturatedsaline, dried with sodium sulfate, and then subjected to distillationoff of the solvent and silica gel purification (hexane/diethyl ether=3/1to 2/1 (volume ratio)), thereby providing the following compound 9-1(140 mg, 0.523 mmol) at a yield of 87%.

The Rf (Relative to Front) value, ¹H NMR spectrum, ¹³C NMR spectrum, IRspectrum, ESI-MS spectrum, ESI-HRMS spectrum, and specific opticalrotation of the obtained compound 9-1 are shown below.

Rf value: 0.3 (hexane/ethyl acetate=4/1 (volume ratio))

¹H NMR (CDCl₃, 400 MHz): δ 7.03 (d, J=3.9 Hz, 1H), 6.18-6.09 (m, 2H),4.61 (m, 1H), 4.42 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 2.76-2.61 (m, 2H),1.42 (s, 9H), 1.29 (t, J=7.1 Hz, 3H)

¹³C NMR (CDCl₃, 100 MHz): δ 166.8, 154.9, 132.7, 131.7, 127.0, 124.8,79.5, 60.6, 43.5, 28.8, 28.4, 14.3

IR (neat, cm¹) 3352, 2978, 1705

ESI-MS m/z 290.1 [M+Na]⁺

ESI-HRMS Calcd for C₁₄H₂₁NO₄Na [M+Na]⁺: 290.1363. Found: 290.1361,

[α]_(D) ²³=−80.5 (34% ee, c=1.00, CHCl₃),

lit.[α]_(D) ²⁰=−217 (>99% ee, c=1.1, CHCl₃) (Bromfield, K. M.; Graden,H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem. Commun. 2007, 3183.)

INDUSTRIAL APPLICABILITY

The compounds of the present invention are intermediates useful forindustrially producing oseltamivir phosphate, and thus can be suitablyused for producing oseltamivir phosphate.

The methods for producing the compound of the present invention canproduce intermediates useful for industrially producing oseltamivirphosphate.

The method for producing oseltamivir phosphate of the present inventionis a production method suitable for industrial production, and can besuitably used for industrially producing oseltamivir phosphate.

Aspects of the present invention are, for example, the following.

<1> A compound represented by the following general formula (1):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom.

<2> A compound represented by the following general formula (5):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom.

<3> A compound represented by the following general formula (6):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, and R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom.

<4> A compound represented by the following general formula (7):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, and R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom.

<5> A compound represented by the following general formula (8):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, and R⁵ represents any of a protective group of an aminogroup, and a hydrogen atom.

<6> A method for producing the compound represented by the generalformula (1) according to <1>, the method including:

reacting together a compound represented by the following generalformula (2), a compound represented by the following general formula(3), and a compound represented by the following general formula (4):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom.

<7> A method for producing the compound represented by the generalformula (5) according to <2>, the method including:

reducing a triple bond of the compound represented by the generalformula (1) according to <1> to a double bond.

<8> A method for producing the compound represented by the generalformula (6) according to <3>, the method including:

cyclizing the compound represented by the general formula (5) accordingto <2>.

<9> A method for producing the compound represented by the generalformula (7) according to <4>, the method including:

reducing a carbonyl group of the compound represented by the generalformula (6) according to <3> to a hydroxyl group.

<10> A method for producing the compound represented by the generalformula (8) according to <5>, the method including:

converting an NR²R³ group of the compound represented by the generalformula (7) according to <4> to an NHR⁵ group wherein R⁵ is a protectivegroup of an amino group, and the protective group R⁵ is different fromR² and R³.

<11> A method for producing a compound represented by the followinggeneral formula (9), the method including:

dehydrating the compound represented by the general formula (8)according to <5> by a dehydration reaction:

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, and R⁵ represents any of a protective group of an aminogroup, and a hydrogen atom.

<12> A method for producing a compound represented by the followinggeneral formula (9), the method including in an order mentioned:

reacting together a compound represented by the following generalformula (2), a compound represented by the following general formula(3), and a compound represented by the following general formula (4) toprovide the compound represented by the general formula (1) according to<1>,

reducing a triple bond of the compound represented by the generalformula (1) to a double bond to provide the compound represented by thegeneral formula (5) according to <2>,

cyclizing the compound represented by the general formula (5) to providethe compound represented by the general formula (6) according to <3>,

reducing a carbonyl group of the compound represented by the generalformula (6) to a hydroxyl group to provide the compound represented bythe general formula (7) according to <4>,

converting an NR²R³ group of the compound represented by the generalformula (7) to an NHR⁵ group, wherein R⁵ is a protective group of anamino group, and the protective group R⁵ is different from R² and R³, toprovide the compound represented by the general formula (8) according to<5>, and

dehydrating the compound represented by the general formula (8) by adehydration reaction to provide the compound represented by thefollowing general formula (9):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom,

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, and R⁵ represents any of a protective group of an aminogroup, and a hydrogen atom.

<13> A method for producing oseltamivir phosphate, the method including:

the method for producing the compound represented by the general formula(1) according to <6>, the method for producing the compound representedby the general formula (5) according to <7>, the method for producingthe compound represented by the general formula (6) according to <8>,the method for producing the compound represented by the general formula(7) according to <9>, the method for producing the compound representedby the general formula (8) according to <10>, or the method forproducing the compound represented by the general formula (9) accordingto <11>, or any combination thereof.

What is claimed is:
 1. A compound represented by the following generalformula (1):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R¹represents any of a protective group of a carboxyl group, and a hydrogenatom.
 2. A compound represented by the following general formula (5):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom.
 3. A method for producing a compound represented by the followinggeneral formula (1), the method comprising: reacting together a compoundrepresented by the following general formula (2), a compound representedby the following general formula (3), and a compound represented by thefollowing general formula (4):

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom,

wherein R¹ represents any of a protective group of a carboxyl group, anda hydrogen atom, R² and R³ each independently represent any of aprotective group of an amino group, and a hydrogen atom, and R⁴represents any of a protective group of a carboxyl group, and a hydrogenatom.